Tri-substituted imidazoles for the inhibition of tgf beta and methods of treatment

ABSTRACT

Pharmaceutical compounds, their methods of manufacture, and methods of treatment of mammals with pharmaceutical compounds are provided.

FIELD OF THE DISCLOSURE

This disclosure relates to small molecular weight substituted imidazolesthat inhibit the TGF-β signaling pathway. More specifically, thisdisclosure relates to methods of using said substituted imidazoles forthe treatment of diseases related to the TGF-β signaling pathwaysincluding, but not limited to, atherosclerosis, Marfan syndrome,Loeys-Dietz syndrome, obesity, diabetes, multiple sclerosis,keratoconus, idiopathic pulmonary fibrosis, Alzheimer's Disease, chronickidney disease, and scleroderma.

The compounds disclosed herein may be especially applicable to thetreatment of various oncology indications, including, but not limitedto, lung cancer, gastric cancer, myelodysplastic syndrome (MDS),melanoma, colon cancer, renal cancer, and preferably glioblastoma (GBM),pancreatic cancer, and hepatocellular carcinoma (HCC). These diseasesmay be treated in mammals, including domesticated quadrupeds andpreferably humans The compounds of the present disclosure may be activein inhibiting the kinase domains of the Type I receptors (ACVR1B, alsoknown as ALK4, TGFβR1, also known as ALK5, BMPR1A, also known as ALK3,BMPR1B, also known as ALK6, and ACVR1C, also known as ALK7) and/or theType II receptors (ACVR2A, ACVR2B, BMPR2, and TGFβRII).

BACKGROUND

The TGFβ signaling pathway is known to regulate a number of cellularprocesses involving growth, differentiation, development, migration, andapoptosis. TGF-β superfamily ligands, including TGF-β1, TGF-β2, andTGF-β3, bind to various combinations of Type I and Type II receptors inoverall hexameric complexes consisting of two identical ligands bound toa heterotetrameric receptor complex, ultimately resulting in thephosphorylation of the Type I receptor and subsequent phosphorylationand activation of SMAD2/SMAD3 intracellular signaling proteins. Thecascade thus initiated results in further activation of downstreamsignaling elements ultimately activating a number of nucleartransduction proteins controlling transcription. The signaling pathwaycomprised of TGF-β/ALK5 combinations is especially important in oncologyindications, and may be disrupted by blocking the key kinase domain ofthe ALK5 receptor.

Despite the existence of known ALK5 inhibitors, additional classes ofcompounds are needed to probe potential efficacy in the diverse diseasesmentioned above, particularly in the area of oncology. Improvements overexisting inhibitors could include, but not be limited to, greatertherapeutic indices, more favorable formulation or biopharmaceuticalproperties, or more optimized tissue distribution. The compounds of thepresent disclosure are believed to have utility in treating the diseasesdescribed above.

SUMMARY

The present invention provides substituted imidazoles for the inhibitionof the TGF-β signaling pathway and methods for treating diseaseemploying said compounds.

DETAILED DESCRIPTION

As described above, this disclosure includes small molecular weightsubstituted imidazoles that may inhibit the TGF-β signaling pathways.More specifically, this disclosure relates to methods of using saidsubstituted imidazoles for the treatment of diseases related to theTGF-β signaling pathways including, but not limited to, atherosclerosis,Marfan syndrome, Loeys-Dietz syndrome, obesity, diabetes, multiplesclerosis, keratoconus, idiopathic pulmonary fibrosis, Alzheimer'sDisease, chronic kidney disease, and scleroderma.

The compounds disclosed herein therefore, may be especially applicableto the treatment of various oncology indications, including, but notlimited to, lung cancer, gastric cancer, myelodysplastic syndrome (MDS),melanoma, colon cancer, renal cancer, and preferably glioblastoma (GBM),pancreatic cancer, and hepatocellular carcinoma (HCC). These diseasesmay be treated in mammals, including domesticated quadrupeds andpreferably humans. The compounds within the present disclosure may beactive in inhibiting the kinase domains of the Type I receptors (ACVR1B,also known as ALK4, TGFβR1, also known as ALK5, BMPR1A, also known asALK3, BMPR1B, also known as ALK6, and ACVR1C, also known as ALK7) and/orthe Type II receptors (ACVR2A, ACVR2B, BMPR2, and TGFβRII).

Compounds of the invention include compounds as embodied by thestructure below and all pharmaceutically acceptable salts, hydrates, orother solvates thereof:

In various embodiments of this disclosure, R¹ may be selected from thegroup consisting of a group represented by the formula —X—Y—Z, theformula —X—Z, the formula —Y—Z, or the formula —Z wherein;

X represents O; NR⁵; S; CR⁶R⁷; C═O; C═S; or an alkyl chain containing 1to 6 carbon atoms;

Y represents O, NR⁵, S, CR⁶R⁷, C═O, C═S, or an alkyl chain containing 1to 6 carbon atoms,

-   -   R⁵ represents hydrogen; aryl; heteromonocyclic; heterobicyclic;        an alkyl chain containing 1 to 6 carbon atoms; an alkenyl chain        containing 1 to 6 carbon atoms; or an alkynyl chain containing 1        to 6 carbon atoms;    -   R⁶ represents hydrogen; or an alkyl chain containing 1 to 6        carbon atoms;    -   R⁷ represents hydrogen; an alkyl chain containing 1 to 6 carbon        atoms; an alkenyl group containing 1 to 6 carbon atoms; an        alkynyl chain containing 1 to 6 carbon atoms; or an alkoxy group        containing 1 to 6 carbon atoms;

Z represents:

-   -   a phenyl group;    -   a substituted phenyl group or substituted heteromonocyclic group        where 1 to 5 substituents are selected from a group consisting        of halogens, alkyl groups containing 1 to 6 carbon atoms,        alkenyl groups containing 1 to 6 carbon atoms, alkynyl groups        containing 1 to 6 carbon atoms, a phenyl group, a pyridyl group,        alkoxy groups containing 1 to 6 carbon atoms, a hydroxyl group,        an amido group, a carbamoyl group, and a cyano group;        -   a hydrogen atom;        -   an alkyl group containing 1 to 12 carbon atoms;        -   an alkenyl group containing 2 to 12 carbon atoms;        -   an alkynyl group containing 1 to 6 carbon atoms;        -   a cycloalkyl group containing 3 to 7 carbon atoms;        -   an alkyl group containing 1 to 12 carbon atoms substituted            by an alkenyl group containing 1 to 6 carbon atoms, an            alkynyl group containing 1 to 6 carbon atoms, an alkoxy            group containing 1 to 6 carbon atoms, a hydroxyl group, an            alkoxyphenylalkoxy group having 8 to 12 carbon atoms, a            morpholino group, a piperidinyl group, a pyrrolidino group,            or a cyclic ether containing 3 to 6 carbon atoms; an alkyl            group having 1 to 6 carbon atoms substituted with 1 to 5            halogen atoms;        -   a cycloalkyl group containing 3 to 9 carbon atoms            substituted with an oxo group;        -   a heteromonocyclic or heterobicyclic group;        -   a heteromonocyclic or a heterobicyclic group substituted            with 1 to 5 members selected from a group consisting of            halogens, alkyl groups containing 1 to 6 carbon atoms,            alkenyl groups containing 1 to 6 carbon atoms, alkynyl            groups containing 1 to 6 carbon atoms, alkoxy groups            containing 1 to 6 carbon atoms, a hydroxyl group, an amido            group, a carbamoyl group, a cyano group, or specifically a            tetrahydropyranyl group;        -   a tetrahydrofuranyl group;        -   a 4-piperidinyl group;        -   a piperidinyl group substituted with an alkyl group            containing 1 to 6 carbon atoms;        -   a t-butoxycarbonyl group;        -   a cyclohexanespiro-2′-(1,3-dioxoranyl) group; or        -   a pyrrolidin-2-one-5-yl group.

In various embodiments of this disclosure, R² may represent:

a hydrogen atom;

an alkyl group containing 1 to 6 carbon atoms;

an alkenyl group containing 1 to 6 carbon atoms;

an alkynyl group containing 1 to 6 carbon atoms,

a cycloalkyl group containing 3 to 7 carbon atoms;

an alkyl group containing 1 to 6 carbon atoms, substituted with acycloalkyl group containing 3 to 7 carbon atoms;

an alkyl group containing 1 to 6 carbon atoms, substituted with 2 to 7halogens;

a phenylalkyl group containing 7 to 12 carbon atoms; or

a phenylalkyl group containing 7 to 12 carbon atoms, substituted with ahydroxyl group, an alkoxy group containing 1 to 6 carbon atoms, analkoxy group containing 1 to 6 carbon atoms substituted with an alkoxygroup containing 1 to 6 carbon atoms, or an alkoxy group having 1 to 6carbon atoms substituted with an alkylamino group containing 1 to 6carbon atoms;

R³ may represent:

a phenyl group;

a phenyl group substituted with 1 to 5 members selected from a groupconsisting of halogens, alkyl groups containing 1 to 6 carbon atoms,alkenyl groups containing 1 to 6 carbon atoms, alkynyl groups containing1 to 6 carbon atoms, alkoxy groups containing 1 to 6 carbon atoms, aphenyl group, a pyridyl group, a hydroxyl group, an amido group, acarbamoyl group, and a cyano group;

a heteromonocyclic or heterobicyclic group;

a heteromonocyclic or a heterobicyclic group substituted with 1 to 5members selected from a group consisting of halogens, alkyl groupscontaining 1 to 6 carbon atoms, a phenyl group, a pyridyl group, alkoxygroups containing 1 to 6 carbon atoms, a hydroxyl group, an amido group,a carbamoyl group, and a cyano group; or

a substituted 3H-quinazolin-4-one.

R⁴ may represent:

a hydrogen atom;

an alkyl group containing 1 to 12 carbon atoms;

an alkenyl group containing 1 to 6 carbon atoms;

an alkynyl group containing 1 to 6 carbon atoms;

a cycloalkyl group containing 3 to 7 carbon atoms;

a cyclic ether containing 3 to 6 carbon atoms;

an alkyl group containing 1 to 12 carbon atoms substituted by an alkoxygroup containing 1 to 6 carbon atoms, a hydroxyl group, analkoxyphenylalkoxy group having 8 to 12 carbon atoms, a morpholinogroup, a piperidinyl group, a pyrrolidino group, or a cyclic ethercontaining 3 to 6 carbon atoms;

an alkyl group having 1 to 6 carbon atoms substituted with 1 to 7halogen atoms;

a cycloalkyl group containing 3 to 9 carbon atoms substituted with anoxo group;

a tetrahydropyranyl group;

a tetrahydrofuranyl group; or

a 4-piperidinyl group.

As used herein, the term “halogen” may be understood to include afluorine, chlorine, bromine, or an iodine atom.

The term “alkyl” may be understood to include a saturated aliphatichydrocarbon containing a specified number of carbon atoms in either astraight-chain or branched-chain configuration. Examples include, butare not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl,isobutyl, sec-butyl, tert-butyl, n-pentyl, neopentyl, n-hexyl, andn-heptyl. Alkyl groups may be optionally substituted with one or moresubstituents including groups such as alkoxy, cycloalkoxy, amino, nitro,cyano, carboxy, halogen, hydroxyl, sulfonyl, or mercapto.

The term “alkenyl” may be understood to refer to an unsaturatedaliphatic hydrocarbon group containing a specified number of carbonatoms, in either a straight-chain or branched-chain configuration, andat least one double bond. Examples include, but are not limited toethylene, propylene, isopropylene, butylene, isobutylene, sec-butylene,tert-butylene, n-pentylene, n-hexylene, and n-heptylene. As used herein,alkenyl groups may be substituted with one or more substituentsincluding groups such as alkoxy, cycloalkoxy, heterocycloalkoxy,aryloxy, heteroaryloxy, aralkyloxy, heteroarylalkoxy, amino, nitro,cyano, carboxy, halogen, hydroxyl, sulfonyl, mercapto, alkylsulfanyl,alkylsulfimyl, alkylsulfonyl, aminocarbonyl (amido), alkylcarbonylamino,cycloalkylcarbonylamino, cycloalkylalkylcarbonylamino,heteroarylcarbonylamino, heteroaralkylcarbonylamino, urea, thiourea,sulfamoyl, sulfamide, alkoxycarbonyl, or alkylcarbonyloxy.

As used herein, the term “alkynyl” may be understood to refer to anunsaturated aliphatic group containing a specified number of carbonatoms in either a straight-chain or branched-chain configuration and atleast one triple bond. Examples include, but are not limited to, ethyne,propyne, butyne, pentyne, hexyne, and heptyne. Alkynyl groups may besubstituted with one or more substituents including groups such asalkoxy, cycloalkoxy, heterocycloalkoxy, aryloxy, heteroaryloxy,aralkyloxy, heteroarylalkoxy, amino, nitro, cyano, carboxy, halogen,hydroxyl, sulfonyl, mercapto, alkylsulfanyl, alkylsulfimyl,alkylsulfonyl, aminocarbonyl (amido), alkylcarbonylamino,cycloalkylcarbonylamino, cycloalkylalkylcarbonylamino,heteroarylcarbonylamino, heteroaralkylcarbonylamino, urea, thiourea,sulfamoyl, sulfamide, alkoxycarbonyl, or alkylcarbonyloxy.

As used herein, the term “cycloalkyl” may be understood to refer to analiphatic carbocyclic ring of 3 to 10 carbon atoms. Examples ofcycloalkyl groups include, but are not limited to, cyclopropyl,cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, adamanyl,norbomyl, octahydroindenyl, decahydronaphthyl, bicycle[3.2.1]octyl, andbicycle[2.2.1]octyl.

As used herein, the term “alkoxy” may be understood to refer to anoxygen-linked alkyl group.

As used herein, the term “heteromonocyclic” may be understood to referto an aromatic or non-aromatic 3 to 8 atom heterocyclic ring systemconsisting of a single ring containing at least one heteroatom (e.g.nitrogen, oxygen, or sulfur) with the balance of the atoms in the ringconsisting of carbon and/or other heteroatoms. Examples ofheteromonocyclic groups include, but are not limited to, aziridine,azetidine, pyrrolidine, piperadine, piperazine, oxetane, furan,tetrahydrofuran, pyran, tetrahydropyran, pyrrole, imidazole, pyrazole,pyridine, pyridazine, pyrazine, pyrimidine, triazine, thiazole,isothiazole, oxazole, isoxazole, thiadiazole, oxadiazole, and triazole.

As used herein, the term “heterobicyclic” may be understood to refer toan aromatic or non-aromatic 7 to 12 atom heterocyclic ring systemconsisting of two fused rings containing at least one heteroatom (e.g.nitrogen, oxygen, or sulfur) with the balance of the atoms in the ringconsisting of carbon and/or other heteroatoms. Examples ofheterobicyclic groups include, but are not limited to, indole,benzimidazole, indazole, benzotriazole, benzoxazole, benzothiazole,pyrrolopyridine, pyrrolopyrimidine, pyrrolopyrazine, pyrrolopyridazine,pyrazolopyridine, pyrazolopyrimidine, pyrazolopyrazine,pyrazolopyridazine, imidazopyridine, imidazopyrimidine (purine),imidazopyrazine, imidazopyridazine, methyenedioxybenzene,triazolopyridine, triazolopyrimidine, quinoline, isoquinoline,cinnoline, phthalazine, quinazoline, quinoxaline, naphthyridine,azaquinazoline, azaquinoxaline, and azanaphthydridine.

It will be understood that the amount of the compound actuallyadministered will be determined by a physician, in the light of therelevant circumstances, including the condition to be treated, thechosen route of administration, the actual compound or compoundsadministered, the age, weight, and response of the individual patient,and the severity of the patient's symptoms.

As used herein, a “subject” refers to an animal that is the object oftreatment, observation or experiment. “Animal” includes cold- andwarm-blooded vertebrates and invertebrates, such as fish, shellfish,reptiles and, in particular, mammals. “Mammal” includes, withoutlimitation, mice; rats; rabbits; guinea pigs; dogs; cats; sheep; goats;cows; horses; primates, such as monkeys, chimpanzees, apes, andprenatal, pediatric, and adult humans.

As used herein, “preventing” or “protecting” means preventing in wholeor in part, or ameliorating, or controlling.

As used herein, the term “treating” refers to both therapeutic treatmentand prophylactic, or preventative, measures, or administering an agentsuspected of having therapeutic potential. The term includespreventative (e.g., prophylactic) and palliative treatment.

The term “a pharmaceutically effective amount”, as used herein, means anamount of active compound, or pharmaceutical agent, that elicits thebiological, or medicinal, response in a tissue, system, animal, or humanthat is being sought, which includes alleviation or palliation of thesymptoms of the disease being treated and/or an amount sufficient tohave utility and provide desired therapeutic endpoint. In the case ofcancer, the therapeutically effective amount of the drug may reduce thenumber of cancer cells; reduce the tumor size; inhibit (i.e., slow tosome extent and preferably stop) cancer cell infiltration intoperipheral organs; inhibit (i.e., slow to some extent and preferablystop) tumor metastasis; inhibit, to some extent, tumor growth; and/orrelieve to some extent one or more of the symptoms associated with thecancer. To the extent the drug may prevent growth and/or kill existingcancer cells, it may be cytostatic and/or cytotoxic. For cancer therapy,efficacy can be measured, e.g., by assessing the time to diseaseprogression and/or determining the response rate.

The term “pharmaceutically acceptable”, as used herein, may beunderstood to include that the substance or composition is compatiblechemically and/or toxicologically, with the other ingredients comprisinga formulation, and/or the mammal being treated therewith.

The term “cancer” may be understood to include the physiologicalcondition in mammals that is typically characterized by unregulated cellgrowth and/or hyperproliferative activities. A “tumor” may include oneor more cancerous cells. Examples of cancer include, but are not limitedto, carcinoma, lymphoma, blastoma, sarcoma, and leukemia or lymphoidmalignancies. In one embodiment, the cancer is a solid tumor.

More particular examples of such cancers include breast cancer, cervicalcancer, ovarian cancer, bladder cancer, endometrial or uterinecarcinoma, prostate cancer, glioma and other brain or spinal cordcancers, squamous cell cancer (e.g., epithelial squamous cell cancer),lung cancer, including small-cell lung cancer, non-small cell lungcancer (“NSCLC”), adenocarcinoma of the lung and squamous carcinoma ofthe lung, cancer of the peritoneum, hepatocellular cancer, gastric orstomach cancer including gastrointestinal cancer, pancreatic cancer,glioblastoma, liver cancer, hepatoma, colon cancer, rectal cancer,colorectal cancer, salivary gland carcinoma, kidney or renal cancer,vulval cancer, thyroid cancer, hepatic carcinoma, anal carcinoma, penilecarcinoma, as well as head and neck cancer.

For example, the following paragraphs describe some preferredembodiments of the present disclosure.

In some preferred embodiments, R¹ may be a hydrogen, methyl,4-benzamido, methyl(3,5-difluorophenyl)amine, ormethyl(o-fluorophenyl)amine.

Some preferred embodiments may include embodiments where R² is eitherhydrogen, 1-(2,2-difluoro)ethyl, or cyclobutyl.

In some embodiments, R³ may be one of the following:

In some embodiments, R⁴ may be a methyl, isopropyl, cyclopropyl,difluoromethyl, or 2,2-difluoroethyl.

Specific compounds of this disclosure, including pharmaceuticallyacceptable salts thereof, include the following compounds (Compound1-Compound 76).

TABLE 1 Expemplary Compounds Com- pound No. Structure and Name 1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

19

20

21

22

23

24

25

26

27

28

29

30

31

32

33

34

35

36

37

38

39

40

41

42

43

44

45

46

47

48

49

50

51

52

53

54

55

56

57

58

59

60

61

62

63

64

65

66

67

68

69

70

71

72

73

74

75

76

It will be recognized by one skilled in the art that basic nitrogenatoms present in the compounds disclosed herein may be combined withorganic or inorganic acids resulting in the formation of salts. Someembodiments encompass an ALK5 inhibitor, as described above, wherein aderivative or a pharmaceutically acceptable salt thereof as the activebiological agent. In addition, solvates comprised of either organic orinorganic solvents may also be prepared and found to be pharmaceuticallyacceptable or even preferable. Many of the compounds disclosed herein,whether as salts or free bases, may exist in one or more crystallineforms. Such polymorphic forms may have differing properties regarding,but not limited to, absorption, solubility, and stability, one or moreof which may be pharmaceutically acceptable or even preferable.

In the case of ALK5 inhibitors that are to be administered orally,blending of the active ingredient with pharmaceutically acceptablecarriers (e.g. excipients, disintegrants, binders, colorants,flavorings, emulsifiers, coatings, etc.), diluents, or solubilizingagents may provide a finished pharmaceutical product in the form oftablets, granules, powders, capsules, suspensions, syrups, or solutions,some of which may be designed for either quick release or timed releaseof the active drug agent. Similar or different formulations may be usedfor compounds specified for delivery via an intravenous, pulmonary,intramuscular route, or via suppository. One skilled in the art—with theaid of this disclosure—will also appreciate that drug compoundsdisclosed herein may be derivatized as prodrugs designed to release theactive ingredient in the GI system or in plasma. Thus, such prodrugderivatives are within the scope of this disclosure.

It will also be understood by skilled practitioners of the art that thescope of the compounds or synthetic intermediates embodied in theformula above may include molecules containing chiral centers. Thepresent disclosure includes embodiments where such compounds are presentin the form of enantiomers, diastereomers, meso structures, or racemicmixtures.

Generally, it is preferred in some embodiments that compounds disclosedherein, if they are comprised of enantiomers or diastereomers with oneor more chiral centers, the preferred compound will be used as a singleenantiomer or diastereomer. Single enantiomers or diastereomers may beprepared by using enantiomerically or diasteromerically pure startingreagents, or by the use of synthetic transformations known to providecontrol of chirality. Alternatively, racemic or diastereomeric mixturesmay be resolved into enantiomerically or diastereomerically purecomponents through the use of standard chiral separation and/orcrystallization techniques.

Also included in the scope of this disclosure are radiolabeled isomersor derivatives of the compounds of the formula described above that maybe suitable for various in vivo biological studies.

One skilled in the art may prepare compounds of the invention by any ofa number of known synthetic methods beginning with starting materialsavailable from a commercial source or synthesized from simpler availablemolecules.

The following six reaction schemes are provided as various examples forsynthesizing various embodiments of the compounds of the invention. Somecompounds of the disclosure may be synthesized, as described below,where R² and R⁴ are as defined above.

Any formula given herein is also intended to represent unlabeled formsas well as isotopically labeled forms of the compounds. Isotopicallylabeled compounds have structures depicted by the formulas given hereinexcept that one or more atoms are replaced by an atom having a selectedatomic mass or mass number. Examples of isotopes that can beincorporated into compounds of the invention include isotopes ofhydrogen, carbon, nitrogen, oxygen, phosphorous, fluorine, chlorine, andiodine, such as ²H, ³H, ¹¹C, ¹³C, ¹⁴C, ¹⁵N, ¹⁸O, ¹⁷O, ³¹P, ³²P, ³⁵S,¹⁸F, ³⁶Cl, and ¹²⁵I, respectively. Such isotopically labeled compoundsare useful in metabolic studies (for example with ¹⁴C), reaction kineticstudies (with, for example ²H or ³H), detection or imagine techniques[such as positron emission tomography (PET) or single-photon emissioncomputed tomography (SPECT)] including drug or substrate tissuedistribution assays, or in radioactive treatment of patients. Inparticular, an ¹⁸F or ¹¹C labeled compound may be particularly suitablefor PET or SPECT studies. Further, substitution with heavier isotopessuch as deuterium (i.e., ²H) may afford certain therapeutic advantagesresulting from greater metabolic stability, for example increased invivo half-life or reduced dosage requirements. Isotopically labeledcompounds of this invention and prodrugs thereof can generally beprepared by carrying out the procedures disclosed in the schemes or inthe examples and preparations described below by substituting a readilyavailable isotopically labeled reagent for a non-isotopically relatedreagent. Deuteration is particularly appropriate for compoundscontaining methyl or methylene groups

Table 2, below, describes the results of assays carried out on somecompounds of the invention. Exemplified compounds were confirmed toinhibit ALK5 activity in enzyme and cellular assays in the followingassay systems conducted by ThermoFisher in Madison, Wis. according totheir commercially available protocols.

ThermoFisher SelectScreen™ Biochemical Kinase Profiling Service,LanthaScreen™Eu Kinase Binding Assay TGFBR1 (ALK5)

Exemplified compounds were screened in 1% DMSO (final concentration) by3-fold serial dilutions from 10,000 nM to 0.316 nM to produce an IC₅₀ orat single concentrations of 10,000, 1000 and 100 nM according to thefollowing protocol. To low volume, white 384-well plates (GreinerCat#784207) add 160 nL 100× compound in 100% DMSO, 3.84 uL kinase buffer(50 mM HEPES, pH 7.5, 0.01% BRIJ-35, 10 mM MgCl₂, 1 mM EGTA), 8 uL 2×kinase/antibody mixture in kinase buffer (final ALK5 concentration of 5nM; final Eu-anti-GST antibody concentration of 2 nM), 4 uL 4× Tracer#178 in kinase buffer (final concentration of 5 nM). Gently shake theplates for 30 seconds and incubate at room temperature for 1 hour beforereading fluorescence on a plate reader. Percent inhibition wasdetermined compared to DMSO only control (maximal ALK5 tracer binding)and sigmoidal dose response curve fit yielded IC₅₀ values as indicatedin Table 2. For those compounds marked with an asterisk, activity wasevaluated at three concentrations (10000, 1000, 10 nM) and the IC₅₀ isdepicted as less than the lowest concentration producing >50%inhibition.

ThermoFisher SelectScreen™ Cell-Based Pathway Profiling ServiceGeneBLAzer Beta-Lactamase (b1a) Reporter Technology—TGF-Beta 1Stimulated SBE-b1a HEK 293T Cell-Based Assay

SBE-b1a HEK 293T cells were thawed and re-suspended in Assay Media(OPTI-MEM, 0.5% dialyzed FBS, 0.1 mM NEAA, 1 mM Sodium Pyruvate, 100U/mL/100 μg/mL Pen/Strep) to a concentration of 625,000 cells/mL. 32 μLof cell suspension (20,000 cells) was added to each well of a 384-wellPoly-D-Lysine assay plate. Cells in Assay Media were incubated for 16-24hours in the plate at 37° C./5% CO₂ in a humidified incubator. 4 μL of a10× serial dilution of ALK5 inhibitors (10×=100,000-3.16 nM) was addedto appropriate wells of the plate and pre-incubated at 37° C./5% CO₂ ina humidified incubator with cells for 30 minutes. Final concentration ofinhibitor ranged from 10,000 nM to 0.316 nM. 4 μL of 10× TGF-beta 1(final concentration of 0.03 nM) was added to wells containing theinhibitors. The plate was incubated for 5 hours at 37° C./5% CO₂ in ahumidified incubator. 8 μL of 1 μM Substrate Loading Solution was addedto each well and the plate was incubated for 2 hours at room temperaturebefore being read on a fluorescence plate reader. Percent inhibition wasdetermined compared to DMSO only control (maximal TGF-beta 1stimulation) and sigmoidal dose response curve fit yielded IC₅₀ valuesas indicated in Table 2. For those compounds marked with an asterisk,activity was evaluated at three concentrations (10000, 1000, and 100 nM)and the IC₅₀ is depicted as less than the lowest concentration producinggreater than 50% inhibition.

TABLE 2 Biological activity assay results Cells Compound (SBE_HEK293T)TβRI (ALK5) Binding No. IC50 (nM) IC50 (nM)  2 >10000 1370  4 >100001370  6 3870 354  8 >10000 811 10 2665 264 12 >10000 — 14 >10000 — 16*3570 <1000 17* — <1000 20* 1270 <100 22* 1090 <100 24* 1930 <200 26* —<100 27* — <100 28* 757 <100 29* 4620 <100 31* 8930 <1000 33* 9120 <20034 379 49 36 507 103 37 53.2 5.6 38* 3180 <100 39 53.6 46.4 40* 1050<100 41 77.5 33 42* — <1000 43* 485 <100 44 37.4 6.66 45* 323 <100 4611.6 5.6 47 19.5 6.6 48* — <100 49* — <1000 50 1070 138 51 — 260 53* —<1000 54 211 31.2 55 132 4.71 56 1050 43.6 57 2190 128 58 3920 78 59 —889 60 — 71.7 61 65.3 7.55 62 1130 45.8 63 3030 399 64 632 44.6 65 65446.2 66 1360 285 67 — 50 68 10.9 1.2 69 — 3

Scheme 1

In Scheme 1 illustrated below, compound (I), which is a subset of thecompounds of the invention, where substituent R¹¹ may be a halogen,alkyl group, etc. as defined by R¹ above, may be prepared beginning withan ester of structure (II), where R¹⁰=alkyl (most typically methyl orethyl). Ester (II) may be reacted with acetal (III) in a suitablesolvent to provide amidine (IV), which may then be reacted withhydroxylamine, followed by trifluoroacetic acid anhydride and thensodium bicarbonate, to provide ester (V). Ester (V) may be converted toits corresponding Weinreb amide (VI) by hydrolysis to the correspondingcarboxylic acid, treatment with thionyl chloride, and reaction of theresultant acid chloride with methoxymethylamine. Reaction of amide (VI)with Grignard reagent (VIII), derived in turn from the reaction ofmagnesium metal with halopyrazole (VII), provides ketone (IX). Invarious embodiments, the halogen of (VII) may be either chloro, bromo,or iodo. Oxidation of (IX) with hydrobromic acid in dimethyl sulfoxide(DMSO) produces diketone (X). Other oxidizing reagents to affect thisconversion include selenium dioxide or nitric acid.

Scheme 2

Another method of making intermediate (X) is shown in Scheme 2 andbegins with the Sonogashira palladium-catalyzed coupling of5-iodo-1,3,3a-triazaindene (XIII) with trimethylsilylacetylene, followedby de-silylation with potassium carbonate to provide alkyne (XIV). Asecond Sonogashira coupling with iodopyrazole (XV) then gives alkyne(XVI), which upon treatment with potassium permanganate followed bysodium nitrite in sulfuric acid, provides intermediate diketone (X). InScheme 1, the condensation of (X) with glyoxal dimethyl acetal providesacetal (XI), which upon treatment with a suitable aqueous acid such ashydrochloric acid provides the aldehyde (XII). Reductive amination withan appropriate substituted aniline followed by treatment with a reducingagent such as sodium borohydride gives compound (I). One skilled in theart will appreciate that the intermediate aldehyde (XII) represents aconvenient advanced intermediate for the preparation of furthercompounds disclosed herein where R³ is specified as a1,3,3a-triazainden-5-yl group.

Scheme 3

Scheme 3 shows the synthesis of compound (XXII) beginning with iodide(XVII). As described above, for the synthesis of compound (X) in Scheme2, two successive Sonogashira reactions may be used to make compound(XIX), which is then oxidized to the diketone (XX). Cyclization of (XX)with ammonium acetate and an appropriate benzaldehyde (XXI) in aceticacid gives final compound (XXII). As described above, R¹¹ may representhalogen, alkyl group, etc. as defined by R1 above. Those skilled in theart will appreciate that the intermediate diketone (XX) may represent aconvenient advanced intermediate for the preparation of furthercompounds disclosed where R³ is specified as a 1,3-benzothiazol-6-ylgroup.

Scheme 4

Scheme 4 shows the preparation of compound (XXXIII) beginning with thereaction of pyrazole aldehyde (XXIII) with p-toluenesulfinic acid (XXIV)in the presence of formamide and trimethylsilyl chloride. The resultingtosylate (XXV) may then be treated with phosphoryl chloride to give theisonitrile (XXVI). Pyridazine (XXVII) may be treated withdimethylformamide dimethyl acetal to give the amidine (XXVIII), whichmay in turn be cyclized to compound (XXIX) in a suitable solvent bytreatment with bromoacetonitrile. Palladium (0) catalyzed coupling oftri-n-butylvinylstannane gives olefin (XXX), which may then be oxidizedwith a suitable oxidant, such as osmium tetroxide in the presence ofsodium periodate, to give aldehyde (XXXI). Imine formation with anappropriate amine then supplies compound (XXXII) which, when reactedwith intermediate (XXVI), may give (XXXIII). It will be appreciated byone skilled in the art that the steps outlined in Scheme 4 are generalfor compounds disclosed herein where R¹ is hydrogen.

Scheme 5

Scheme 5 shows an alternate preparation of compound (X), a keyintermediate from Scheme 1, beginning with known aldehyde (XXXIV), whichmay be condensed with aniline and diphenylphosphite to provide the knownadduct (XXXV). Further reaction with pyrazole aldehyde (XXXVI) thenprovides ketone (XXXVII), oxidation of which with hydrobromic acid inDMSO gives dione (X).

Scheme 6

Scheme 6 outlines a Suzuki boronic ester coupling strategy for thepreparation of compound (XI), a key intermediate from Scheme 1,beginning with known aldehyde (XXXVIII). After treatment with acid inmethanol to provide acetal (XXXIX), palladium-catalyzed coupling withknown pinacolboronic ester (XL) gives bromide (XLI). A secondpalladium-catalyzed coupling with pinacolborinic ester (XLII) providesacetal (XI). One skilled in the art will appreciate that intermediate(XXXIX) has an acidic proton in the imidazole ring. This position may beprotected if necessary prior to Suzuki coupling using an appropriategroup such as a [2-(trimethylsilyl)ethoxy]methyl (SEM) moiety.De-protection using tetra-n-butylammonium fluoride or a similar reagentwould then provide the free imidazole at some downstream point in thesynthesis.

EXAMPLES Example 1 Synthesis of Compound 1(N-((5-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-4-(1-methyl-1H-pyrazol-3-yl)-1H-imidazol-2-yl)methyl)-2-fluoroaniline)

Phosphonate i can be synthesized from known aldehyde[1,2,4]triazolo[1,5-a]pyridine-6-carbaldehyde (CAS #614750-81-1)following Preparation 7 (see below). Known phosphonate i (CAS1415663-77-2, 6.0 g, 13.2 mmol) and known aldehyde ii (CAS #27258-32-8,1.75 g, 15.9 mmol) are dissolved in a mixture of dry tetrahydrofuran(112 mL) and dry isopropyl amine (35 mL). Cesium carbonate (6.9 g, 21.2mmol) is added at room temperature, and the resultant mixture stirredfor 20 hours at room temperature until the reaction is complete. Thereaction mixture is cooled to 10° C., and 60 mL of 3N HCl is added. Thereaction is stirred for 2 hours at room temperature, and the mixture isextracted into methyl t-butyl ether. The organic layer is separated andwashed three times with 1N HCl (25 mL). Residual solvent is evaporatedto give iii in 78% yield.

The resulting product (iii, 2.5 g, 10.3 mmol) was dissolved in DMSO (20mL) and cooled to 0° C. Hydrobromic acid (48%, 5 mL, 41.5 mmol) isadded. The reaction is heated to 65° C. and stirred for 2 hours. Aftercooling to 0° C., 10 g of ice is added to the reaction mixture, and thepH adjusted to pH 10 by addition of 10% potassium carbonate. The mixtureis stirred at 10° C. for 10 minutes, and the resultant yellow solid (iv)is filtered and rinsed with ice-cold water (76% yield).

Dione iv (2.0 g, 7.8 mmol) is dissolved in methyl t-butyl ether (40 mL)and dry methanol (20 mL). 2,2-dimethoxy acetaldehyde (1.7 g, 9.6 mmol)and ammonium acetate (60%, 1.5 g, 12 mmol) are added. The reaction isstirred at room temperature for 18 hours, then cooled to 10° C. The pHis adjusted to pH 8-9 via addition of aqueous sodium carbonate. Theresultant mixture is extracted into chloroform (3×50 mL). The organiclayer is washed with water and dried over sodium sulfate before removalof the residual solvent. The resultant brown oil is dissolved in methylt-butyl ether (15 mL) and the solvent is removed. Hexanes (2×20 mL) areadded, and the solvent is decanted to give v in 95% yield.

The resulting solid (v, 2.5 g, 7.4 mmol) is dissolved in 1N HCl (55 mL)and stirred for 3 hours at 70° C. The mixture is cooled to 0° C. and thepH adjusted to 7-8 with aqueous sodium bicarbonate. The solid isseparated and maintained for 30 minutes at 5° C., after which it isfiltered and washed with ice-cold water. Methanol is added, the mixtureis heated to 50° C., then cooled and filtered to give a light brownsolid (aldehyde vi, 83% yield).

Aldehyde vi (1 g, 3.4 mmol) is dissolved in dichloroethane (20 mL).Acetic acid (200 mg, 3.4 mmol) is added, along with 2-fluoro-aniline(vii, 560 mg, 5.1 mmol). The mixture is refluxed for 2 hours, thencooled to 0° C. Methanol (10 mL) and tetrahydrofuran (5 mL) are added,then 538 mg (10.2 mmol) of sodium borohydride are added slowly. Themixture is warmed to room temperature and stirred for 3 hours. Thereaction is cooled to 10° C. and the pH adjusted to pH 7 with 1N HC1.The mixture is extracted into dichloromethane, and the organic layer isdried over sodium sulfate. Residual solvent is removed prior to flashchromatography in 5% methanol in dichloromethane to yield 1 (MS m/zM+1=389.2).

Further compounds that can be prepared essentially according to themethod described above are shown in Table 3:

TABLE 3 Physical Data % (MS, Yield m/z (over- # Structure and NameM + 1) all) 3

371.3 21.4% 5

389.2 16.8% 7

389.2 17.8% 11

405.2 9.7% 13

396.3 14.1% 15

396.2 9.7%

Replacing 1-methyl-1H-pyrazole-3-carbaldehyde (ii) with1-isopropyl-1H-pyrazole-3-carbaldehyde (CAS #1226694-29-6) in the abovesequence provides for the synthesis of the compounds listed in Table 4.

TABLE 4 Physical Data % (MS, Yield m/z (over- # Structure and NameM + 1) all) 9

399.5    9.6% 19

417.3 20% 28

424.2 14% 35

435.4 29%

Example 2 Synthesis of Compound 17(4-(5-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-4-(1-isopropyl-1H-pyrazol-3-yl)-1H-imidazol-2-yl)benzamide)

Starting dione viii (150 mg, 0.53 mmol) is dissolved in methanol (1.5mL) and methyl t-butyl ether (3.0 mL). The reaction is cooled to 15° C.and 4-cyanobenzaldehyde ix (174 mg, 1.325 mmol) and ammonium acetate(102 mg, 1.325 mmol) are added. The reaction is stirred at roomtemperature for 16 hours, and quenched with aqueous sodium bicarbonate(to pH 8). The mixture is extracted into ethyl acetate, and the organiclayer is washed with brine, dried over sodium sulfate, and concentratedto yield desired nitrile x in 23% yield.

Nitrile x (40 mg, 0.10 mmol) is dissolved in concentrated sulfuric acid(1.0 mL) at 10° C., then warmed to room temperature and stirred for 5hours. The reaction is cooled to 0° C., then diluted with ice. Aqueousammonia is added (to pH=8.5), and the mixture is extracted intodichloromethane. The organic layer is washed with brine, dried oversodium sulfate, and concentrated. The product is purified on aluminumoxide, using 5% methanol in dichloromethane as the mobile phase to give17 in 50% yield (MS m/z M+2=414.2)

Example 3 Synthesis of Compound 29(3-(((5-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-4-(1-isopropyl-1H-pyrazol-3-yl)-1H-imidazol-2-yl)methyl)amino)benzamide)

In an alternative method to install the desired amide, nitrile xi (50mg, 0.118 mmol) is dissolved in DMSO (2 mL), and potassium carbonate (18mg, 0.13 mmol) is added, followed by hydrogen peroxide (0.6 mL). Thereaction is heated to 100° C. and stirred for 1 hour. The mixture isdiluted with 10 mL of water and extracted into dichloromethane. Theorganic layer is washed with brine, dried over sodium sulfate, andconcentrated. The crude material is purified on basic aluminum oxidewith 5% methanol in dichloromethane as the mobile phase to give compound29 in trace yield.

Either method of amide installation can be used to complete thesynthesis of compound 18 (below) from compound 15.

TABLE 5 % Yield Physical (from # Structure and Name Data nitrile) 18

414.3 12%

Example 4 Synthesis of diphenyl((3-cyanoimidazo[1,2-b]pyridazin-6-yl)(phenylamino)methyl)phosphonate(xiii)

Known aldehyde xii (see WO 2016/140884, CAS #2001563-08-0) (1.0 g, 5.8mmol) and aniline (550 mg, 5.9 mmol) are added to a dry round bottomflask and stirred for 30 minutes. Isopropanol (2 mL) is added and thereaction stirred for 2 hours at room temperature. Diphenyl phosphite(1.5 mL, 7.5 mmol) is added, and the reaction heated to 45° C. for onehour, then stirred overnight at room temperature. The solvent is removedand the product purified by flash chromatography (10%-30% ethyl acetatein hexanes) to give xiii in 47% yield.

Once synthesized, phosphonate xiii can be treated to the conditionsdescribed in to give compound 27 shown below in Table 6.

TABLE 6 Physical Data % (MS, Yield m/z (over- # Structure and NameM + 1) all) 27

442.3 1.1%

Compound 27 can further be treated using the conditions in Example 3 togive compound 34 shown below in Table 7.

TABLE 7 Physical Data % (MS, Yield m/z (from # Structure and Name M + 1nitrile) 34

460.3 <1%

Example 5 Synthesis of6-(2-formyl-4-(1-isopropyl-1H-pyrazol-3-yl)-1H-imidazol-5-yl)imidazo[1,2-b]pyridazine-3-carboxamide(xv)

The amide is installed earlier in the synthesis using the proceduredescribed in Example 2. For the synthesis of coumpound 37 (below), theprocedure is then completed as described in Example 1.

TABLE 8 Physical Data % (MS, Yield m/z (over- # Structure and NameM + 1) all) 38

467.4 <1%

Example 6 Synthesis of1-(1-isopropyl-1H-pyrazol-3-yl)-2-(quinoxalin-6-yl)ethane-1,2-dione(xix)

Known quinoxaline xvi (CAS # 50998-17-9, 1.0 g, 4.78 mmol) is dissolvedin acetonitrile (20 mL) under inert atmosphere. Triethylamine (6.6 mL,47.8 mmol) is added, followed by known pyrazole xvii (CAS #1354706-26-5, 850 mg, 5.26 mmol) and palladium tetrakis (665 mg, 0.478mmol). The reaction is heated to 70° C. and stirred for 18 hours. Thesolvent is removed by distillation under vacuum at 55° C., and theresultant product is purified by flash chromatography (30% ethyl acetatein petroleum ether) to give xviii in 80% yield.

To a solution of magnesium sulfate (940 mg, 3.82 mmol) and sodiumbicarbonate (80 mg, 0.95 mmol) in water (10 mL) is added a solution ofthe starting material xviii (500 mg, 1.91 mmol) in acetone (20 mL).HighFlow (800 mg) is added (note that Celite could be used as analternative), followed by potassium permanganate (600 mg, 3.82 mmol),and the reaction is stirred for 2 hours. Aqueous sodium carbonate isadded and the reaction mixture is extracted into ethyl acetate. Theresidual solvent is distilled off, and the crude material is washed withmethyl t-butyl ether (2×5 mL) to provide xix in 59% yield.

Once synthesized, xix can be treated to the same conditions shown for ivin Example 1 to continue the sequence and form the compounds shown belowin Table 9.

TABLE 9 Physical Data (MS, m/z % Yield # Structure and Name M + 1)(overall) 21

428.3    6.1% 39

445.2 12% 40

476.3    9.2% 41

435.3    7.1% 45

446.2    3.4% 48

446.3    9.6% 49

462.3    6.5% 50

452.2    3.1% 51

480.2    7.7% 54

444.3    8.3% 57

428.3    3.5% 58

471.3    3.7%

Alternatively, subjecting xix to the conditions shown in Example 2 givesthe exemplary compounds shown in Table 10. Note that, for compounds 42and 43, 3-ethynyl-1-methyl-1H-pyrazole (CAS #61514-59-8) should besubstituted for pyrazole xvii in Example 6.

TABLE 10 Physical Data % (MS, Yield m/z (over # Structure and NameM + 1) -all) 42

378.2   1.2% 43

396.2 <1% 59

424.3   7.1%

Example 7 Synthesis of diphenyl((phenylamino)(quinolin-6-yl)methyl)phosphonate (xxi)

To a round bottom flask under inert atmosphere is added aldehyde xx (CAS#4113-04-6, 50 mg, 0.32 mmol) and aniline (30 mg, 0.32 mmol). Themixture is stirred for 30 minutes and isopropanol (0.25 mL) is added.The reaction is stirred for 2 hours, then diphenyl phosphite (90 mg,0.38 mmol) is added. The reaction is stirred overnight, then filteredand the resultant solid washed with methyl t-butyl ether to give xxi in74% yield.

Once synthesized, xxi can be subjected to the conditions described inExample 1 to give the compounds shown in Table 11. Note that, forcompounds 25 and 32, aldehyde ii should be replaced with1-isopropyl-1H-pyrazole-3-carbaldehyde (CAS #1226694-29-6).

TABLE 11 % Yield Physical (over- # Structure and Name Data all) 23

398.2 <1% 25

427.5 <1% 30

398.2 <1% 32

427.2 <1%

Example 8 Synthesis of1-(benzo[d]thiazol-6-yl)-2-(1-methyl-1H-pyrazol-3-yl)ethane-1,2-dione(xxv)

The synthesis of xxv can be accomplished by subjecting known iodide (CAS#654070-00-5) and known alkyne xxiii (CAS #61514-59-8) to the conditionsdescribed in Example 6. Once in hand, xxv can be used to synthesize thecompounds shown below in Table 12 by using the procedure described inExample 2 to form the nitrile and Example 3 to install the amide.

TABLE 12 Physical Data % (MS, Yield m/z (over- # Structure and NameM + 1) all) 37

401.2 2.7%

Example 9 Synthesis of Compound 44(6-(2-methyl-4-(1-methyl-1H-pyrazol-3-yl)-1H-imidazol-5-yl)benzo[d]thiazole)

Dione xxv (250 mg, 0.73 mmol) is dissolved in acetic acid (10 mL).Acetaldehyde (20%, 500 mg, 1.84 mmol) and ammonium acetate (340 mg, 4.42mmol) are added. The mixture is heated to 100° C. for 2 hours. Water andammonium hydroxide are added, after which the mixture is extracted intodichloromethane, and the solvent is removed. The crude product ispurified by flash column chromatography (4-6% methanol indichloromethane) to give 44 in 27% yield (MS m/z M+1=296.2).

Compound 55 can be synthesized by the same method with the substitutionof formaldehyde for acetaldehyde.

Compounds 52 and 56 are synthesized following the same method, using xix(or the corresponding methyl-substituted derivative) in place of xxv asthe starting material.

Compound 63 can also be synthesized following Example 9, using4-formyl-2,6-dimethylbenzonitrile in place of acetaldehyde, andfollowing Example 2 to install the amide using sulfuric acid.

TABLE 13 Physical Data % (MS, Yield m/z (over- # Structure and NameM + 1) all) 52

305.2 9.1% 55

282.1 3.7% 56

277.2 7.5% 63

429.2 4.9%

Example 10 Synthesis of Compound 62(5-(benzo[d]thiazol-6-yl)-4-(1-methyl-1H-pyrazol-3-yl)-1H-imidazole-2-carboxamide)

Starting dione xxv (200 mg, 0.738 mmol) is dissolved in methanol (2 mL)and tetrahydrofuran (2 mL). Ammonium acetate (570 mg, 7.38 mmol) andethyl glyoxalate (0.23 mL, 1.10 mmol) are added. The reaction is stirredfor 18 hours, then quenched with aqueous sodium sulfite. The mixture isextracted into ethyl acetate, and the organic layer is dried over sodiumsulfate and concentated, followed by purification by flash columnchromatography (5% methanol in dichloromethane) to give xxvi in 35%yield.

Ester xxvi (100 mg, 0.283 mmol) is dissolved in methanolic ammoniasolution (4 mL) in a sealed tube. The reaction is heated at 100° C. for18 hours, followed by concentration under vacuum at 50° C. The crudemixture is purified on neutral aluminum oxide with 3-5% methanol indichloromethane as the mobile phase to give 62 (26% yield, MS m/zM+1=325.2).

Example 11 Synthesis of Compound 64(4-(5-(benzo[d]thiazol-6-yl)-4-(1-methyl-1H-pyrazol-3-yl)-1H-imidazol-2-yl)-N-methylbenzamide)

Starting dione xxv (400 mg, 1.476 mmol) can be treated under theconditions described in Example 9 using 4-formyl benzoic acid instead ofacetaldehyde to give xxvii in 9.5% yield.

Acid xxvii (200 mg, 0.5 mmol) is dissolved in dimethylformamide (3 mL).Carbonyl diimidazole (161 mg, 1.0 mmol) is added. The reaction isstirred for 40 minutes, then triethylamine (0.18 mL) is added, alongwith methylamine hydrochloride (40 mg, 0.60 mmol). The reaction isstirred for a further 2 hours, after which the mixture is extracted intoethyl acetate and the organic layer is concentrated prior topurification by flash column chromatography (3-5% methanol indichloromethane) to provide 64 in 14% yield (MS m/z M+1=415.2).

The same conditions can be used to synthesize the compounds shown below,using ethylamine hydrochloride and dimethylamine hydrochloride,respectively, in place of methylamine hydrochloride.

TABLE 14 Physical Data % (MS, Yield m/z (over- # Structure and NameM + 1) all) 65

429.3 3.0% 66

429.3 4.2%

Example 12 Synthesis of6-((1-(difluoromethyl)-1H-pyrazol-3-yl)ethynyl)quinoxaline (xxx)

Known alkyne xxviii (CAS #442517-33-1) and known iodide (CAS#1394130-21-2) are treated as described in Example 6 to yield alkynexxx. Once in hand, xxx can be oxidized as in Example 6, and used tosynthesize the compounds shown below in Table 15 by following the stepsoutlined in Example 1.

Using known benzothiazole (CAS #864376-04-5) in place of alkyne xxviiipermits the synthesis of compounds 60 and 61.

Replacing the iodide in Example 12 with 1-cyclopropyl-3-iodo-1H-pyrazole(CAS #1616069-72-7) leads to compound 68.

TABLE 15 Physical Data % (MS, Yield m/z (over- # Structure and NameM + 1) all) 46

436.2    1.1% 47

443.2    1.1% 60

419.2 15% 61

437.2 <1% 68

444.3    9.3%

Example 13 Synthesis of3-(benzo[d][1,3]dioxol-5-ylethynyl)-1-methyl-1H-pyrazole

Known bromide xxxi (CAS #2635-13-4) and known alkyne xxiii (CAS#61514-59-8) are subjected to the conditions described in Example 6 tosynthesize alkyne xxxii. Further treatment to oxidize the alkyne as inExample 6, followed by the conditions described in Examples 2 and 3results in the formation of compound 67 (below).

TABLE 16 Physical Data % (MS, Yield m/z (over- # Structure and NameM + 1) all) 67

388.2 6.0%

Example 14 Synthesis of 3-ethynyl-1-isopropyl-1H-pyrazole (xvii, CAS1354706-26-5)

3-Nitro-1H-pyrazole xxxiii (5 g, 44.2 mmol) is dissolved indimethylformamide (50 mL) and cesium carbonate (14 g, 43 mmol) is added.The reaction is stirred for thirty minutes at room temperature, andisopropyl bromide (5 mL, 53.3 mmol) is added. The reaction is stirred atroom temperature for 12 hours, after which watter (100 mL) is added andthe reaction mixture is stirred for 10 minutes. The mixture is extractedinto ethyl acetate (3×100 mL), and the organic layer is washed withbrine and concentrated prior to purification by flash columnchromatography (20% ethyl acetate in hexanes) to give xxxiv in 73%yield.

Pyrazole xxxiv (2 g, 13.98 mmol) is dissolved in methanol (20 mL) andhydrazine (90%, 0.5 mL, 13.98 mmol) is added. Raney nickel (0.5 g) isadded slowly. The temperature is raised to 50° C. for one hour, then thereaction is cooled and the mixture filtered through HighFlow. Thefiltrate is concentrated and purified by flash column chromatography(20% ethyl acetate in hexanes) to give xxxv in 29% yield.

Amine xxxv (10 g, 0.088 mol) is dissolved in t-butanol (80 mL) andp-toluene sulfonic acid (43 g, 0.25 mol) is added and the reaction iscooled to 15° C. A solution of sodium nitrite (12.15 g, 0.17 mol) andpotassium iodide (17.5 g, 0.10 mol) in water (40 mL) is added drop wise.The reaction is then stirred at room temperature for one hour, afterwhich 60 mL of water is added and the mixture is extracted into ethylacetate. The organic layer is washed with aqueous sodium bicarbonate,then dried over sodium sulfate and concentrated. The crude mixture ispurified by flash column chromatography (30% ethyl acetate in hexanes)to give xxxvi in 29% yield.

Iodide xxxvi (2 g, 8.5 mmol) is dissolved in 1,4 dioxane (20 mL) underinert atmosphere and triethylamine (8.8 mL, 63.4 mmol) is added and themixture stirred for 30 minutes. Trimethylsilyl acetate (3.5 mL, 31.5mmol) is added and the reaction is stirred for a further 15 minutes.PdCl₂(PPh₃)₂ (58 mg, 0.08 mmol) and copper (I) iodide (32 mg, (0.17mmol) are added and the reaction is heated to 80° C. for two hours.After cooling to room temperature, the reaction mixture is filteredthrough HighFlow, and the filtrate is dried over sodium sulfate andconcentrated. The crude mixture is purified by flash columnchromatography (0-10% ethyl acetate in hexanes) to give xxxvii in 80%yield.

TMS-alkyne xxxvii (1.5 g, 7.3 mmol) is dissolved in methanol (20 mL)under inert atmosphere and potassium carbonate (1.0 g, 7.3 mmol) isadded. The reaction is stirred at room temperature for 2 hours, thenfiltered. The filtrate is concentrated, and water added beforeextracting the mixture into ethyl acetate. The organic layer is driedover sodium sulfate to give xvii in 71% yield (MS m/z M+1=135.1).

Example 15 Synthesis of 7-bromoquinoxaline-2-carbonitrile (xlv, CAS#1609932-73-1)

Diamine xxxviii (200 g, 1.85 mol) is dissolved in ethanol (1.2 L). Ethylglyoxalate (50% in toluene, 450 mL) is added dropwise. The reaction isheated to 50° C. for 12 hours, then cooled to 5° C. for 1 hour. Themixture is filtered and the solid washed with water to give xxxix in 92%yield.

Quinoxalone xxxix (250 g, 1.7 mol) is dissolved in acetic acid (4500mL). A mixture of acetic acid (988 mL) and bromine (108 mL, 2.1 mol) isadded dropwise, and the mixture stirred at room temperature for 12hours, then heated to 60° C. for 12 hours. After cooling to roomtemperature, the reaction is filtered and the solid washed with water.The wet cake (500 g) is then dissolved in 1500 mL of methanol and heatedto 60° C., then filtered and dried at 60° C. to give xl in 85% yield.

Phosphorous oxychloride (500 mL, 5.34 mol) is placed in a round bottomflask, followed by bromide xl (112 g, 0.50 mol) and dimethylformamide (7mL). The reaction is heated to 120° C. for 2 hours, then the phosphorousoxychloride is removed under vacuum. The reaction is poured onto icewater and the resultant solid is filtered and washed with water. The wetcake is dissolved in ethyl acetate, and the organic layer is filteredthrough HighFlow and dried over sodium sulfate before beingconcentrated. Hexanes are added and the solid filtered, then dried at50° C. under vacuum to give xli in 57% yield.

Chloride xli (50 g, 0.21 mol) is dissolved in toluene (1000 mL) underinert atmosphere and stirred for 15 minutes. Tributyl(vinyl) tin (65 g,0.21 mol) and palladium tetrakis (2.5 g, 0.02 mol) is added. Thereaction is heated to 90° C. for 18 hours. The mixture is cooled to roomtemperature, then filtered through HighFlow and washed with ethylacetate. The organic layer is washed with water, then dried over sodiumsulfate and concentrated. The crude mixture is purified by flash columnchromatography (20% ethyl acetate in hexanes) to give xlii in 61% yield.

Allyl xlii (60 g, 0.26 mol) is dissolved in tetrahydrofuran (1250 mL)and water (396 mL). Osmium tetroxide (2 g, 0.0078 mol) is added, and thereaction is cooled of 0° C. Sodium periodate (121 g, 0.64 mol) in water(850 mL) is added dropwise. The reaction is stirred for 4 hours, thenethyl acetate is added and the reaction is stirred for 30 minutes. Theorganic layer is separated, and the aqueous layer is extracted intoethyl acetate. The combined organic layers are washed with water anddried over sodium sulfate and concentrated to give xliii in 32% yield.

Aldehyde xliii (2.0 g, 8.4 mmol) is placed in a round bottom flask, andhydroxylamine sulfate (1.4 g, 8.5 mmol) in water (6.0 mL) are added. Thereaction is cooled to −15° C., and sodium hydroxide (0.35 g, 8.7 mmol)in water (3.2 mL) are added. The reaction is stirred for 2 hours, thenextracted into ethyl acetate. The organic layer is dried over sodiumsulfate and concentrated to give hydroxylamine xliv in 94% yield.

Hydroxylamine xliv (2.0 g, 7.93 mmol) and phosphorous oxychloride (20mL, (21.4 mmol) are heated to 120° C. for 2 hours, after which thesolvent is completely removed under vacuum. The remaining mixture ispoured onto ice water, and the pH is adjusted to 7 using aqueous sodiumbicarbonate. The mixture is extracted into ethyl acetate, and theorganic layer is dried over sodium sulfate and concetrated to givenitrile xlv in 48% yield.

Example 16 Synthesis of7-((1-isopropyl-1H-pyrazol-3-yl)ethynyl)quinoxaline-2-carbonitrile(xlvi)

Nitrile xlv and alkyne xvii are coupled as described in Example 6.Following oxidation of alkyne xlvi (Example 6), the synthesis ofcompound 75 (below) is completed by following the sequence in Example 1and installation of the amide using sulfuric acid as in Example 2.

In a prophetic example, use of 6-iodoquinazoline (CAS #848841-54-3) and1-cyclopropyl-3-iodo-1H-pyrazole (CAS #1616069-72-7) in place of xlv andxvii permits the synthesis of compound 72.

TABLE 17 Physical Data (MS, m/z % Yield # Structure and Name M + 1)(overall) 75

471.2 1.6%7-(2-(((3,5-difluorophenyl)amino)methyl)-4-(1-isopropyl-1H-pyrazol-3-yl)-1H-imidazol-5-yl)quinoxaline-2-carboxamide 72

N-((4-(1-cyclopropyl-1H-pyrazol-3-yl)-5-(quinazolin-6-yl)-1H-imidazol-2-yl)methyl)-3,5-difluoroaniline

Example 17 Synthesis of Compound 70(6-(4-(1-cyclopropyl-1H-pyrazol-3-yl)-2-(((3,5-difluorophenyl)amino)methyl)-1H-imidazol-5-yl)imidazo[1,2-a]pyridine-3-carboxamide)

In a prophetic example, aldehyde xlvii can be treated to the conditionsabove using known boronic ester (CAS #1989745-33-6) to give acetal 1. Asecond coupling gives lii, which can be subjected to the conditionsdescribed in Example 1 followed by amide hydrolysis as in Example 2 togive compound 70, shown below.

6-(4-(1-cyclopropyl-1H-pyrazol-3-yl)-2-(((3,5-difluorophenyl)amino)methyl)-1H-imidazol-5-yl)imidazo[1,2-a]pyridine-3-carboxamideExample 18 Synthesis of Compound 73(6-(4-(1-cyclopropyl-1H-pyrazol-3-yl)-2-(((3,5-difluorophenyl)amino)methyl)-1H-imidazol-5-yOquinazolin-4-ol)

In a prophetic example, known boronic ester liii (CAS #363185-87-9) canundergo Suzuki coupling with bromide liv to give lv. Following treatmentwith formamide to yield lvi, the conditions described above in Scheme 6can be applied to yield compound 73, shown below.

6-(4-(1-cyclopropyl-1H-pyrazol-3-yl)-2-(((3,5-difluorophenyl)amino)methyl)-1H-imidazol-5-yl)quinazolin-4-ol

In a further prophetic example shown below using known boronic esterlvii (CAS #1209485-71-1) is coupled to bromide lviii via the samemethod.

This method permits the synthesis of compound 76, shown below.

6-(4-(1-cyclopropyl-1H-pyrazol-3-yl)-2-(((3,5-difluorophenyl)amino)methyl)-1H-imidazol-5-yl)-3-methylquinazolin-4(3H)-oneExample 18 Synthesis of Compound 75(4-(4-(1-cyclopropyl-1H-pyrazol-3-yl)-2-(((3,5-difluorophenyl)amino)methyl)-1H-imidazol-5-yl)quinoline-6-carboxamide)

In a prophetic example, 4-bromoquinoline-6-carbonitrile (CAS#642477-82-5) can be converted to the corresonding alkyne and, alongwith 1-cyclopropyl-3-iodo-1H-pyrazole (CAS #1616069-72-7) subjected tothe conditions described in Example 12 to ultimately yield compound 75(below).

4-(4-(1-cyclopropyl-1H-pyrazol-3-yl)-2-(((3,5-difluorophenyl)amino)methyl)-1H-imidazol-5-yl)quinoline-6-carboxamide Example 19 Formation ofHydrochloride (HCl) Salt

Compound 1 is dissolved in methanolic hydrochloric acid, heated to 45°C., and stirred for 1 hour. The solution is concentrated, and theresultant solid is washed with petroleum ether (3 mL) followed by methylt-butyl ether (2×3 mL), and dried to give 2.

This procedure can be used in the synthesis of the HCl salts shown belowin Table 18.

TABLE 18 % No. Structure and Name Yield 2

80%N-((5-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-4-(1-methyl-1H-pyrazol-3-yl)-1H-imidazol-2-yl)methyl)-2-fluoroaniline hydrochloride 4

76%N-((5-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-4-(1-methyl-1H-pyrazol-3-yl)-1H-imidazol-2-yl)methyl)aniline hydrochloride 6

62%N-((5-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-4-(1-methyl-1H-pyrazol-3-yl)-1H-imidazol-2-yl)methyl)-3-fluoroaniline hydrochloride 8

54%N-((5-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-4-(1-methyl-1H-pyrazol-3-yl)-1H-imidazol-2-yl)methyl)-4-fluoroaniline hydrochloride 10

62%N-((5-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-4-(1-isopropyl-1H-pyrazol-3-yl)-1H-imidazol-2-yl)methyl)aniline hydrochloride 12

41%N-((5-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-4-(1-methyl-1H-pyrazol-3-yl)-1H-imidazol-2-yl)methyl)-4-chloroaniline hydrochloride 14

<1%N-((5-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-4-(1-methyl-1H-pyrazol-3-yl)-1H-imidazol-2-yl)methyl)-4-chloroaniline hydrochloride 16

24%3-(((5-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-4-(1-methyl-1H-pyrazol-3-yl)-1H-imidazol-2-yl)methyl)amino)benzonitrile hydrochloride 20

81%N-((5-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-4-(1-isopropyl-1H-pyrazol-3-yl)-1H-imidazol-2-yl)methyl)-3-fluoroaniline hydrochloride 22

16%3-fluoro-N-((4-(1-isopropyl-1H-pyrazol-3-yl)-5-(quinoxalin-6-yl)-1H-imidazol-2-yl)methyl)aniline hydrochloride 26

27%3-fluoro-N-((4-(1-isopropyl-1H-pyrazol-3-yl)-5-(quinolin-6-yl)-1H-imidazol-2-yl)methyl)aniline hydrochloride 31

16%2-fluoro-N-((4-(1-methyl-1H-pyrazol-3-yl)-5-(quinolin-6-yl)-1H-imidazol-2-yl)methyl)aniline hydrochloride 33

27%2-fluoro-N-((4-(1-isopropyl-1H-pyrazol-3-yl)-5-(quinolin-6-yl)-1H-imidazol-2-yl)methyl)aniline hydrochloride 36

13%N-((5-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-4-(1-isopropyl-1H-pyrazol-3-yl)-1H-imidazol-2-yl)methyl)-3,5-difluoroaniline hydrochloride 53

 7% 6-(4-(1-isopropyl-1H-pyrazol-3-yl)-1H-imidazol-5-yl)quinoxalinehydrochloride

I claim:
 1. A compound of the formula:

wherein R¹ is selected from the group consisting of a group of theformula —X—Y—he formula —X—Z, the formula —Y—Z, and the formula —Zwherein; X is O; NR⁵; S; CR⁶R⁷; C═O; C═S; or an alkyl chain containing 1to 6 carbon atoms; Y is O, NR⁵, S, CR⁶R⁷, C═O, C═S, or an alkyl chaincontaining 1 to 6 carbon atoms, R⁵ is hydrogen; aryl; heteromonocyclic;heterobicyclic; an alkyl chain containing 1 to 6 carbon atoms; analkenyl chain containing 1 to 6 carbon atoms; or an alkynyl chaincontaining 1 to 6 carbon atoms; R⁶ is hydrogen; or an alkyl chaincontaining 1 to 6 carbon atoms; R⁷ is hydrogen; an alkyl chaincontaining 1 to 6 carbon atoms; an alkenyl group containing 1 to 6carbon atoms; an alkynyl chain containing 1 to 6 carbon atoms; or analkoxy group containing 1 to 6 carbon atoms; Z is a phenyl group; asubstituted phenyl group or substituted heteromonocyclic group where 1to 5 substituents are selected from a group consisting of halogens,alkyl groups containing 1 to 6 carbon atoms, alkenyl groups containing 1to 6 carbon atoms, alkynyl groups containing 1 to 6 carbon atoms, aphenyl group, a pyridyl group, alkoxy groups containing 1 to 6 carbonatoms, a hydroxyl group, an amido group, a carbamoyl group, and a cyanogroup; a hydrogen atom; an alkyl group containing 1 to 12 carbon atoms;an alkenyl group containing 2 to 12 carbon atoms; an alkynyl groupcontaining 1 to 6 carbon atoms; a cycloalkyl group containing 3 to 7carbon atoms; an alkyl group containing 1 to 12 carbon atoms substitutedby an alkenyl group containing 1 to 6 carbon atoms, an alkynyl groupcontaining 1 to 6 carbon atoms, an alkoxy group containing 1 to 6 carbonatoms, a hydroxyl group, an alkoxyphenylalkoxy group having 8 to 12carbon atoms, a morpholino group, a piperidinyl group, a pyrrolidinogroup, or a cyclic ether containing 3 to 6 carbon atoms; an alkyl grouphaving 1 to 6 carbon atoms substituted with 1 to 5 halogen atoms; acycloalkyl group containing 3 to 9 carbon atoms substituted with an oxogroup; a heteromonocyclic or heterobicyclic group; a heteromonocyclic ora heterobicyclic group substituted with 1 to 5 members selected from agroup consisting of halogens, alkyl groups containing 1 to 6 carbonatoms, alkenyl groups containing 1 to 6 carbon atoms, alkynyl groupscontaining 1 to 6 carbon atoms, alkoxy groups containing 1 to 6 carbonatoms, a hydroxyl group, an amido group, a carbamoyl group, a cyanogroup, or specifically a tetrahydropyranyl group; a tetrahydrofuranylgroup; a 4-piperidinyl group; a piperidinyl group substituted with analkyl group containing 1 to 6 carbon atoms; a t-butoxycarbonyl group; acyclohexanespiro-2′-(1,3-dioxoranyl) group; and a pyrrolidin-2-one-5-ylgroup; R² is a hydrogen atom; an alkyl group containing 1 to 6 carbonatoms; an alkenyl group containing 1 to 6 carbon atoms; an alkynyl groupcontaining 1 to 6 carbon atoms, a cycloalkyl group containing 3 to 7carbon atoms; an alkyl group containing 1 to 6 carbon atoms, substitutedwith a cycloalkyl group containing 3 to 7 carbon atoms; an alkyl groupcontaining 1 to 6 carbon atoms, substituted with 2 to 7 halogens; aphenylalkyl group containing 7 to 12 carbon atoms; or a phenylalkylgroup containing 7 to 12 carbon atoms, substituted with a hydroxylgroup, an alkoxy group containing 1 to 6 carbon atoms, an alkoxy groupcontaining 1 to 6 carbon atoms substituted with an alkoxy groupcontaining 1 to 6 carbon atoms, or an alkoxy group having 1 to 6 carbonatoms substituted with an alkylamino group containing 1 to 6 carbonatoms; R³ is a phenyl group; a phenyl group substituted with 1 to 5members selected from a group consisting of halogens, alkyl groupscontaining 1 to 6 carbon atoms, alkenyl groups containing 1 to 6 carbonatoms, alkynyl groups containing 1 to 6 carbon atoms, alkoxy groupscontaining 1 to 6 carbon atoms, a phenyl group, a pyridyl group, ahydroxyl group, an amido group, a carbamoyl group, and a cyano group; aheteromonocyclic or heterobicyclic group; and a heteromonocyclic or aheterobicyclic group substituted with 1 to 5 members selected from agroup consisting of halogens, alkyl groups containing 1 to 6 carbonatoms, a phenyl group, a pyridyl group, alkoxy groups containing 1 to 6carbon atoms, a hydroxyl group, an amido group, a carbamoyl group, or acyano group; or a substituted 3H-quinazolin-4-one. R⁴ is a hydrogenatom; an alkyl group containing 1 to 12 carbon atoms; an alkenyl groupcontaining 1 to 6 carbon atoms; an alkynyl group containing 1 to 6carbon atoms; a cycloalkyl group containing 3 to 7 carbon atoms; acyclic ether containing 3 to 6 carbon atoms; an alkyl group containing 1to 12 carbon atoms substituted by an alkoxy group containing 1 to 6carbon atoms, a hydroxyl group, an alkoxyphenylalkoxy group having 8 to12 carbon atoms, a morpholino group, a piperidinyl group, a pyrrolidinogroup, or a cyclic ether containing 3 to 6 carbon atoms; an alkyl grouphaving 1 to 6 carbon atoms substituted with 1 to 7 halogen atoms; acycloalkyl group containing 3 to 9 carbon atoms substituted with an oxogroup; a tetrahydropyranyl group; a tetrahydrofuranyl group; or a4-piperidinyl group; and pharmaceutically acceptable salts, hydrates orsolvates thereof.
 2. The compound of claim 1 that is selected from thegroup consisting of:

and pharmaceutically acceptable salts, hydrates and solvates thereof. 3.The compound of claim 1 that is selected from the group consisting of:

and pharmaceutically acceptable salts, hydrates and solvates thereof. 4.The compound of claim 1 that is:

and pharmaceutically acceptable salts, hydrates and solvates thereof. 5.The compound of claim 1 that is:

and pharmaceutically acceptable salts, hydrates and solvates thereof. 6.The compound of claim 1 that is:

and pharmaceutically acceptable salts, hydrates and solvates thereof. 7.The compound of claim 1 that is:

and pharmaceutically acceptable salts, hydrates and solvates thereof. 8.The compound of claim 1 that is:

and pharmaceutically acceptable salts, hydrates and solvates thereof. 9.The compound of claim 1 that is:

and pharmaceutically acceptable salts, hydrates and solvates thereof.10. The compound of claim 1 that is:

and pharmaceutically acceptable salts, hydrates and solvates thereof.11. The compound of claim 1 that is:

and pharmaceutically acceptable salts, hydrates and solvates thereof.12. The compound of claim 1 that is:

and pharmaceutically acceptable salts, hydrates and solvates thereof.13. The compound of claim 1 that is:

and pharmaceutically acceptable salts, hydrates and solvates thereof.14. The compound of claim 1 that is:

and pharmaceutically acceptable salts, hydrates and solvates thereof.15. The compound of claim 1 that is:

and pharmaceutically acceptable salts, hydrates and solvates thereof.16. The compound of claim 1, wherein the compound is selected from thegroup consisting of: Compound No. Structure and Name 1

N-((5-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-4-(1-methyl-1H-pyrazol-3-yl)-1H-imidazol-2-yl)methyl)-2-fluoroaniline 2

N-((5-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-4-(1-methyl-1H-pyrazol-3-yl)-1H-imidazol-2-yl)methyl)-2-fluoroaniline hydrochloride 3

N-((5-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-4-(1-methyl-1H-pyrazol-3-yl)-1H-imidazol-2-yl)methyl)aniline 4

N-((5-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-4-(1-methyl-1H-pyrazol-3-yl)-1H-imidazol-2-yl)methyl)aniline hydrochloride 5

N-((5-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-4-(1-methyl-1H-pyrazol-3-yl)-1H-imidazol-2-yl)methyl)-3-fluoroaniline 6

N-((5-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-4-(1-methyl-1H-pyrazol-3-yl)-1H-imidazol-2-yl)methyl)-3-fluoroaniline hydrochloride 7

N-((5-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-4-(1-methyl-1H-pyrazol-3-yl)-1H-imidazol-2-yl)methyl)-4-fluoroaniline 8

N-((5-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-4-(1-methyl-1H-pyrazol-3-yl)-1H-imidazol-2-yl)methyl)-4-fluoroaniline hydrochloride 9

N-((5-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-4-(1-isopropyl-1H-pyrazol-3-yl)-1H-imidazol-2-yl)methyl)aniline 10

N-((5-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-4-(1-isopropyl-1H-pyrazol-3-yl)-1H-imidazol-2-yl)methyl)aniline hydrochloride 11

N-((5-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-4-(1-methyl-1H-pyrazol-3-yl)-1H-imidazol-2-yl)methyl)-4-chloroaniline 12

N-((5-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-4-(1-methyl-1H-pyrazol-3-yl)-1H-imidazol-2-yl)methyl)-4-chloroaniline hydrochloride 13

2-(((5-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-4-(1-methyl-1H-pyrazol-3-yl)-1H-imidazol-2-yl)methyl)amino)benzonitrile 14

2-(((5-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-4-(1-methyl-1H-pyrazol-3-yl)-1H-imidazol-2-yl)methyl)amino)benzonitrile hydrochloride 15

3-(((5-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-4-(1-methyl-1H-pyrazol-3-yl)-1H-imidazol-2-yl)methyl)amino)benzonitrile 16

3-(((5-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-4-(1-methyl-1H-pyrazol-3-yl)-1H-imidazol-2-yl)methyl)amino)benzonitrile hydrochloride 17

4-(5-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-4-(1-isopropyl-1H-pyrazol-3-yl)-1H-imidazol-2-yl)benzamide 18

3-(((5-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-4-(1-methyl-1H-pyrazol-3-yl)-1H-imidazol-2-yl)methyl)amino)benzamide 19

N-((5-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-4-(1-isopropyl-1H-pyrazol-3-yl)-1H-imidazol-2-yl)methyl)-3-fluoroaniline 20

N-((5-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-4-(1-isopropyl-1H-pyrazol-3-yl)-1H-imidazol-2-yl)methyl)-3-fluoroaniline hydrochloride 21

3-fluoro-N-((4-(1-isopropyl-1H-pyrazol-3-yl)-5-(quinoxalin-6-yl)-1H-imidazol-2-yl)methyl)aniline 22

3-fluoro-N-((4-(1-isopropyl-1H-pyrazol-3-yl)-5-(quinoxalin-6-yl)-1H-imidazol-2-yl)methyl)aniline hydrochloride 23

3-fluoro-N-((4-(1-methyl-1H-pyrazol-3-yl)-5-(quinolin-6-yl)-1H-imidazol-2-yl)methyl)aniline24

3-fluoro-N-((4-(1-methyl-1H-pyrazol-3-yl)-5-(quinolin-6-yl)-1H-imidazol-2-yl)methyl)aniline hydrochloride 25

3-fluoro-N-((4-(1-isopropyl-1H-pyrazol-3-yl)-5-(quinolin-6-yl)-1H-imidazol-2-yl)methyl)aniline26

3-fluoro-N-((4-(1-isopropyl-1H-pyrazol-3-yl)-5-(quinolin-6-yl)-1H-imidazol-2-yl)methyl)aniline hydrochloride 27

6-(2-(((3-fluorophenyl)amino)methyl)-4-(1-isopropyl-1H-pyrazol-3-yl)-1H-imidazol-5-yl)imidazo[1,2-b]pyridazine-3-carbonitrile 28

3-(((5-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-4-(1-isopropyl-1H-pyrazol-3-yl)-1H-imidazol-2-yl)methyl)amino)benzonitrile 29

3-(((5-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-4-(1-isopropyl-1H-pyrazol-3-yl)-1H-imidazol-2-yl)methyl)amino)benzamide 30

2-fluoro-N-((4-(1-methyl-1H-pyrazol-3-yl)-5-(quinolin-6-yl)-1H-imidazol-2-yl)methyl)aniline31

2-fluoro-N-((4-(1-methyl-1H-pyrazol-3-yl)-5-(quinolin-6-yl)-1H-imidazol-2-yl)methyl)aniline hydrochloride 32

2-fluoro-N-((4-(1-isopropyl-1H-pyrazol-3-yl)-5-(quinolin-6-yl)-1H-imidazol-2-yl)methyl)aniline33

2-fluoro-N-((4-(1-isopropyl-1H-pyrazol-3-yl)-5-(quinolin-6-yl)-1H-imidazol-2-yl)methyl)anilinehydrochloride 34

6-(2-(((3-fluorophenyl)amino)methyl)-4-(1-isopropyl-1H-pyrazol-3-yl)-1H-imidazol-5-yl)imidazo[1,2-b]pyridazine-3-carboxamide 35

N-((5-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-4-(1-isopropyl-1H-pyrazol-3-yl)-1H-imidazol-2-yl)methyl)-3,5-difluoroaniline 36

N-((5-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-4-(1-isopropyl-1H-pyrazol-3-yl)-1H-imidazol-2-yl)methyl)-3,5-difluoroaniline hydrochloride 37

4-(5-(benzo[d]thiazol-6-yl)-4-(1-methyl-1H-pyrazol-3-yl)-1H-imidazol-2-yl)benzamide38

6-(2-(((3-cyanophenyl)amino)methyl)-4-(1-isopropyl-1H-pyrazol-3-yl)-1H-imidazol-5-yl)imidazo[1,2-b]pyridazine-3-carboxamide 39

3,5-difluoro-N-((4-(1-isopropyl-1H-pyrazol-3-yl)-5-(quinoxalin-6-yl)-1H-imidazol-2-yl)methyl)aniline 40

N-((4-(1-isopropyl-1H-pyrazol-3-yl)-5-(quinoxalin-6-yl)-1H-imidazol-2-yl)methyl)-3-(1H-pyrazol-1-yl)aniline 41

3-(((4-(1-isopropyl-1H-pyrazol-3-yl)-5-(quinoxalin-6-yl)-1H-imidazol-2-yl)methyl)amino)benzonitrile 42

4-(4-(1-methyl-1H-pyrazol-3-yl)-5-(quinoxalin-6-yl)-1H-imidazol-2-yl)benzonitrile43

4-(4-(1-methyl-1H-pyrazol-3-yl)-5-(quinoxalin-6-yl)-1H-imidazol-2-yl)benzamide44

6-(2-methyl-4-(1-methyl-1H-pyrazol-3-yl)-1H-imidazol-5-yl)benzo[d]thiazole45

2,5-difluoro-N-((4-(1-isopropyl-1H-pyrazol-3-yl)-5-(quinoxalin-6-yl)-1H-imidazol-2-yl)methyl)aniline 46

N-((4-(1-(difluoromethyl)-1H-pyrazol-3-yl)-5-(quinoxalin-6-yl)-1H-imidazol-2-yl)methyl)-3-fluoroaniline 47

3-(((4-(1-(difluoromethyl)-1H-pyrazol-3-yl)-5-(quinoxalin-6-yl)-1H-imidazol-2-yl)methyl)amino)benzonitrile 48

3,4-difluoro-N-((4-(1-isopropyl-1H-pyrazol-3-yl)-5-(quinoxalin-6-yl)-1H-imidazol-2-yl)methyl)aniline 49

4-chloro-3-fluoro-N-((4-(1-isopropyl-1H-pyrazol-3-yl)-5-(quinoxalin-6-yl)-1H-imidazol-2-yl)methyl)aniline 50

3-fluoro-5-(((4-(1-isopropyl-1H-pyrazol-3-yl)-5-(quinoxalin-6-yl)-1H-imidazol-2-yl)methyl)amino)benzonitrile 51

3,4-dichloro-N-((4-(1-isopropyl-1H-pyrazol-3-yl)-5-(quinoxalin-6-yl)-1H-imidazol-2-yl)methyl)aniline 52

6-(4-(1-isopropyl-1H-pyrazol-3-yl)-1H-imidazol-5-yl)quinoxaline 53

6-(4-(1-isopropyl-1H-pyrazol-3-yl)-1H-imidazol-5-yl)quinoxalinehydrochloride 54

3-chloro-N-((4-(1-isopropyl-1H-pyrazol-3-yl)-5-(quinoxalin-6-yl)-1H-imidazol-2-yl)methyl)aniline 55

6-(4-(1-methyl-1H-pyrazol-3-yl)-1H-imidazol-5-yl)benzo[d]thiazole 56

6-(4-(1-methyl-1H-pyrazol-3-yl)-1H-imidazol-5-yl)quinoxaline 57

2-fluoro-N-((4-(1-isopropyl-1H-pyrazol-3-yl)-5-(quinoxalin-6-yl)-1H-imidazol-2-yl)methyl)aniline 58

3-fluoro-5-(((4-(1-isopropyl-1H-pyrazol-3-yl)-5-(quinoxalin-6-yl)-1H-imidazol-2-yl)methyl)amino)benzamide 59

4-(4-(1-isopropyl-1H-pyrazol-3-yl)-5-(quinoxalin-6-yl)-1H-imidazol-2-yl)benzamide60

4-(5-(benzo[d]thiazol-6-yl)-4-(1-(difluoromethyl)-1H-pyrazol-3-yl)-1H-imidazol-2-yl)benzonitrile 61

4-(5-(benzo[d]thiazol-6-yl)-4-(1-(difluoromethyl)-1H-pyrazol-3-yl)-1H-imidazol-2-yl)benzamide 62

5-(benzo[d]thiazol-6-yl)-4-(1-methyl-1H-pyrazol-3-yl)-1H-imidazole-2-carboxamide63

4-(5-(benzo[d]thiazol-6-yl)-4-(1-methyl-1H-pyrazol-3-yl)-1H-imidazol-2-yl)-3,5-dimethylbenzamide 64

4-(5-(benzo[d]thiazol-6-yl)-4-(1-methyl-1H-pyrazol-3-yl)-1H-imidazol-2-yl)-N-methylbenzamide 65

4-(5-(benzo[d]thiazol-6-yl)-4-(1-methyl-1H-pyrazol-3-yl)-1H-imidazol-2-yl)-N-ethylbenzamide66

4-(5-(benzo[d]thiazol-6-yl)-4-(1-methyl-1H-pyrazol-3-yl)-1H-imidazol-2-yl)-N,N-dimethylbenzamide 67

4-(5-(benzo[d][1,3]dioxol-5-yl)-4-(1-methyl-1H-pyrazol-3-yl)-1H-imidazol-2-yl)benzamide68

N-((4-(1-cyclopropyl-1H-pyrazol-3-yl)-5-(quinoxalin-6-yl)-1H-imidazol-2-yl)methyl)-3,5-difluoroaniline 69

N-((5-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-4-(1-cyclopropyl-1H-pyrazol-3-yl)-1H-imidazol-2-yl)methyl)-3,5-difluoroaniline 70

6-(4-(1-cyclopropyl-1H-pyrazol-3-yl)-2-(((3,5-difluorophenyl)amino)methyl)-1H-imidazol-5-yl)imidazo[1,2-a]pyridine-3-carboxamide 71

7-(4-(1-cyclopropyl-1H-pyrazol-3-yl)-2-(((3,5-difluorophenyl)amino)methyl)-1H-imidazol-5-yl)quinoxaline-2- carboxamide72

N-((4-(1-cyclopropyl-1H-pyrazol-3-yl)-5-(quinazolin-6-yl)-1H-imidazol-2-yl)methyl)-3,5-difluoroaniline 73

6-(4-(1-cyclopropyl-1H-pyrazol-3-yl)-2-(((3,5-difluorophenyl)amino)methyl)-1H-imidazol-5-yl)quinazolin-4-ol 74

6-(4-(1-cyclopropyl-1H-pyrazol-3-yl)-2-(((3,5-difluorophenyl)amino)methyl)-1H-imidazol-5-yl)imidazo[1,2-b]pyridazine-3-carboxamide 75

4-(4-(1-cyclopropyl-1H-pyrazol-3-yl)-2-(((3,5-difluorophenyl)amino)methyl)-1H-imidazol-5-yl)quinoline-6-carboxamide 76

6-(4-(1-cyclopropyl-1H-pyrazol-3-yl)-2-(((3,5-difluorophenyl)amino)methyl)-1H-imidazol-5-yl)-3-methylquinazolin-4(3H)-one

and pharmaceutically acceptable salts, hydrates and solvates thereof.17. A method for treating a disease in mammals comprising administeringa therapeutically effective amount of a compound of claim 1 to a mammalin need of treatment.
 18. The method of claim 17, wherein the disease isselected from the group consisting of atherosclerosis, Marfan syndrome,Loeys-Dietz syndrome, obesity, diabetes, Multiple Sclerosis,keratoconus, idiopathic pulmonary fibrosis, Alzheimer's Disease, chronickidney disease, chronic obstructive pulmonary disease (COPD), asthma,congestive heart failure, ischemic heart attack, and scleroderma. 19.The method of claim 17, wherein the disease is selected from the groupconsisting of lung cancer, gastric cancer, myelodysplastic syndrome(MDS), melanoma, colon cancer, renal cancer, glioblastoma (GBM),pancreatic cancer, myelofibrosis, multiple myeloma, esophageal cancer,head and neck squamous carcinoma, ovarian carcinoma, endometrial cancer,cholangiocarcinoma, sarcoma, medulloblastoma, NSCLC, breast cancer, andhepatocellular carcinoma (HCC).